Dipeptidyl peptidase IV (DPPIV) is a serine protease which specifically hydrolyzes dipeptide X-Pro from the free N-terminus of polypeptide chains.
Glucose-dependent insulin-release stimulating hormones secreted from the intestinal tract after meals, that is, incretins (GLP-1, glucagon-like peptide-1, and GIP, glucose-dependent insulinotropic polypeptide) are degraded and inactivated rapidly by DPPIV. It is shown that the suppression of this degradation due to DPPIV enhances the action by incretins (GLP-1 and GIP) and increases insulin secretion from pancreas β-cells resulting from glucose stimulation, resulting in improvement in high levels of blood glucose after oral glucose tolerance tests (Diabetologia, 1999, November 42(11):1324–31). It is also shown that GLP-1 is involved in effects of suppressing appetite and amounts of eating, and has protecting action of the β-cells based on promoting the differentiation and proliferation of pancreas β-cells.
Thus, it is likely expected that DPPIV inhibitors can be useful agents for the treatment and prophylaxis of diseases, such as obesity and diabetes, in which GLP-1 and GIP are involved.
In addition, many publications report the relationship between various diseases and dipeptidyl peptidase IV as described below, and therefore it is also likely expected that DPPIV inhibition can provide agents for their treatment:
(1) agents for the prophylaxis and treatment of AIDS (Science, 262, 2045–2050, 1993);
(2) agents for the prophylaxis and treatment of osteoporosis (Clinical Chemistry, 34, 2499–2501, 1988);
(3) agents for the prophylaxis and treatment of intestinal disorders (Endocrinology, 141, 4013–4020, 2000);
(4) agents for the prophylaxis and treatment of diabetes, obesity, and hyperlipemia (Diabetes, 47, 1663–1670, 1998; Life Sci., 66(2), 91–103, 2000);
(5) agents for the prophylaxis and treatment of neovascularization (Agents and Actions, 32, 125–127, 1991);
(6) agents for the prophylaxis and treatment of infertility (WO 00/56296);
(7) agents for the prophylaxis and treatment of inflammatory disorders, autoimmune disease, and rheumatoid arthritis (J. Immunology, 166, 2041–2048, 2001); and
(8) agents for the prophylaxis and treatment of cancers (Br J. Cancer, 1999, March, 79(7–8), 1042–8; J. Androl., March–April., 21(2), 220–6(2000)).
1-Carbamoylazole derivatives are known to be useful as herbicides, as described in U.S. Pat. Nos. 3,308,131, 5,258,361, 5,338,720, 5,424,279 and 5,510,320; and Japanese Patent Application Laid-open (JP-A) Nos. 5-255318, 9-143181 and 11-80137, but there is no report on DPPIV inhibiting effects.
DDPIV inhibitors are disclosed in, for example, U.S. Pat. Nos. 5,543,396, 6,011,155 and 6,303,661; US-A1-20010020006; and WO 00/34241. However, they are distinctly different in structure from those of the present invention.